The renin-angiotensin system (RAS) plays a pivotal role in vasoconstriction, sodium reabsorption and kidney development. Moreover, RASE is involvements in cardiovascular and renal tissue remodeling. Not long ago, angiotensin II (Ang II) was believed to be produced mainly in the pulmonary vessels and delivered to other tissues via plasma. Instead, Ang II is now thought to be produced in the vicinity of its receptors by local renin and Ang I converting enzyme (ACE). While a variety of extrarenal tissues are now recognized to have the potential for synthesizing renin, the functional role of such local RAS is yet to be established. This is because it is difficult to evaluate the functional significance of local versus systemic RAS in vivo, although indirect evidence suggests distinct regulation of systemic (circulating) and local (renal) RAS. Thus, in most experimental models and human disease in which ACE inhibitors attenuate progression of renal failure, circulating (plasma) renin is not unregulated. Recently, the PI established an in vivo system for ~regionally nullifying~ a gene of interest whereby adjacent areas within the same organ, including the heart and kidney, either possess or are devoid of expression of the gene of interest. The projects proposed here will utilize conventional as well as the new regionally-mutated mice to evaluate the PI~s hypotheses that alternative renin substrates exist; that local intra- adrenal (not circulating) renin regulates aldosterone synthesis and Ang II-dependent functions in the kidney are regulated by renal (not circulating) renin. The PI will evaluate pathophysiologic settings, testing the hypothesis that progressive parenchymal renal damage depends on local RAS whereas parenchymal cardiac disease depends on circulating (not local) RAS.